TECHNICAL AND REGULATORY HURDLES IN DELIVERY ASPECTS OF MACROMOLECULAR DRUGS

Although this meeting attests to the importance of continuing progress in the development of novel delivery systems for macromolecular pharm aceuticals, only one such product has been approved for marketing - DN ase, which is delivered by aerosol. This situation is the result of th e significant number of obstacles in the commercialization of potentia l delivery systems. In addition to the obvious financial commitment a company must make to their development, there are new technical challe nges and novel concerns from regulatory bodies who must approve the sy stems. For protein macromolecular drugs (here, arbitrarily defined as greater than or equal to 10 000 MW) the advances in analytical methodo logy, stimulated by regulatory requirements concerning recombinant DNA derived products, focus attention on changes in the drug caused by th e chemical components or manufacturing processes in the preparation of the new dosage forms. Thus, for a marketed product for which a new de livery system is contemplated (for example, a sustained release formul ation of somatropin), extensive characterization of the 'delivered' pr oduct will be required. The extent to which preclinical or clinical wo rk needs to be repeated will depend on the changes From the existing p roduct caused by the delivery system. In addition, altered pharmacokin etic, pharmacodynamic or distribution profiles will require additional clinical evaluation to assess equivalence or superiority, depending o n the rationale behind the new delivery mode. Somewhat paradoxically, if a new macromolecular entity must be delivered by a novel delivery s ystem in order to be effective, it will only be subject to 'single' sc rutiny, on its own merits. Emerging therapies based on DNA, such as an ti-sense, 'naked' DNA, complexed DNA or viral vectors, will require co mparable development and application of analytical methodologies for p roduction and quality control as was seen during the emergence of rDNA derived protein therapies. This presentation will discuss many of the se principles and illustrate their application in some examples of the development of delivery systems for rDNA derived protein pharmaceutic als.